Patient Disposition and Baseline Characteristics
A total of 149 patients were enrolled in the study, of whom 147 (98.7%) formed the SS and 111 (74.5%) the FAS. Most enrolled patients (68.5%) followed the study to completion (Fig. 1).
In the SS, most patients were female (68.7%) and the mean (SD) age of participants was 55.6 (11.9) years. About three quarters (75.5%) of the SS were aged less than 65 years and the majority of patients (70.1%) were undergoing concomitant treatment with MTX (Table 1). In the FAS, most patients had high (73.9%) or moderate (23.4%) disease activity at baseline, as measured by DAS28(ESR) (Table 1).
DAS28(ESR) Response Rates at Week 78 by Week 12 Responder Status
At week 12, 80 patients (72.1%) were DAS28(ESR) responders and 31 (27.9%) were non-responders. These data were used to divide patients into two groups—week 12 responders and week 12 non-responders—which formed the basis for all subsequent effectiveness analyses.
At week 78, a greater proportion of week 12 responders [43.8%, n = 35 (95% CI 32.7, 55.3)] than non-responders [22.6%, n = 7 (9.6, 41.1)] had a DAS28(ESR) response (Fig. 2). Subgroup analyses suggested that this trend was consistent between genders: among men, week 78 response rate was 50.0% (n = 12) in week 12 responders and 0% in non-responders, while in women, it was 41.1% (n = 23) and 33.3% (n = 7), respectively. Analysis by age group indicated a similar pattern: among patients aged less than 65 years, week 78 response rate was 40.0% (n = 24) in week 12 responders and 26.1% (n = 6) in non-responders, while in those aged 65 years or more, it was 55.0% (n = 11) and 12.5% (n = 1), respectively.
Similar trends were evident upon subgroup analysis by RF status and ACPA presence. For example, in RF-positive patients, week 78 response was 48.9% (n = 22) in week 12 responders and 11.1% (n = 2) in week 12 non-responders, while in RF-negative patients, the proportions were 41.2% (n = 7) and 30.0% (n = 3), respectively (Supplementary Fig. 1). Similarly, in ACPA-positive patients, the week 78 response rate was 33.3% (n = 9) in week 12 responders and 18.2% (n = 2) in week 12 non-responders, while in ACPA-negative patients, it was 42.1% (n = 8) and 20.0% (n = 2), respectively (Supplementary Fig. 1).
Secondary Effectiveness Outcomes
On average, the mean change from baseline in DAS28(ESR), HAQ-DI, and RADAI scores was greater among week 12 responders than non-responders, across all relevant time points (Fig. 3).
Similarly, a greater proportion of week 12 responders met the criteria for a “good” EULAR response at week 78 [41.3% (n = 33), compared to 16.1% (n = 5) of non-responders], while a greater proportion of week 12 non-responders failed to meet the EULAR response criteria [45.2% (n = 14), compared to 18.8% (n = 15) of responders]. The proportions of week 12 responders and non-responders who met the criteria for a “moderate” EULAR response were approximately equal (Fig. 4).
Other Effectiveness Outcomes
The mean length of hospitalization during the study was comparable between week 12 responders (3.13 days) and non-responders (2.33 days), although the mean number of concomitant medical procedures was greater among non-responders (5.0 versus 1.0) (Supplementary Table 1). Overall, there was little change in employment status in either group, and improvements in workplace and household productivity were comparable (Supplementary Tables 2 and 3).
At baseline, the PASS response was “No” (indicating an unacceptable symptom state, from the patient’s perspective) for 91.0% (n = 101) of patients, and “Yes” for 9.0% (n = 10) of patients. By week 12, however, more than half of patients (55.9%, n = 62) indicated satisfaction with their present symptom state. In each subsequent visit, the majority of week 12 responders had an acceptable PASS response. Moreover, the proportion of week 12 responders with an acceptable PASS response consistently exceeded that of non-responders (Supplementary Table 4).
The mean overall EQ-5D score improved from 49.38 at baseline to 60.63 at week 12 (mean change from baseline 11.68) and remained fairly consistent through to week 78. Among week 12 responders, the greatest mean change from baseline was at week 12 (15.10) and was comparable at week 78 (13.45). By contrast, week 12 non-responders reported little change from baseline in EQ-5D score at weeks 12 and 26 (2.92 and 3.08, respectively), with an increase at week 52 (10.96) that declined again by week 78 (6.72) (Supplementary Table 5).
The median duration of exposure to CZP in this study was 606.5 days (range 70–786 days). Overall, nine patients (6.1%) experienced 13 ADRs (Table 2).
Two cases of pulmonary tuberculosis were reported in this study. One was in a 52-year-old man, who developed tuberculosis approximately 26 months after initiation of CZP. The patient was considered negative for tuberculosis at screening . The event resolved following 6 months’ treatment with rifampicin, isoniazid, ethambutol, and pyridoxine. CZP was then restarted, and the patient completed the study. The reporting physician considered the event to be related to CZP. No further information was available regarding the patient’s medical history, prior tuberculosis status, or the medical testing, evaluation, or treatment of his tuberculosis, and there was insufficient documentation to confirm that the pathogen was Mycobacterium tuberculosis.
The second case was in a 59-year-old woman, who had a medical history notable for RA and hepatic steatosis, and developed pulmonary tuberculosis approximately 12 months after CZP initiation. The patient was started on Rifinah® (rifampicin/isoniazid), pyrazinamide, ethambutol, and pyridoxine for 2 months, and then reduced to Rifinah® and pyridoxine for 4 months. The tuberculosis was considered resolved approximately 7 months after diagnosis and starting treatment, and the patient restarted on CZP. The reporting physician considered the event to be related to CZP. No further information was available regarding the patient’s prior tuberculosis status.
There was also one case of cellulitis, which was considered related to CZP and led to treatment discontinuation, and one of bladder cancer, for which causality was not known. No deaths were reported during this study.